Several industrial scale processes are known for the preparation of hydantoin of the Formula ##STR3##
According to E. Ware [Chem.Rev. 46, 403 (1950)] glycine ethyl ester or glycine nitrile is reacted with potassium cyanate, or glycine nitrile or lactic acid nitrile is treated with ammonium carbonate and the hydantoinic acid intermediate thus obtained is converted into hydantoin by acidic cyclization. Hydantoin is also formed by melting glycine and urea, while the reaction can be accomplished with nitro urea in aqueous solution too. The reaction of various amino acids (i.e. glycine) with urea in aqueous solution in the presence of barium hydroxide was studied. The first step of the synthesis of .beta.-aryl amino acids starting from hydantoin is the condensation reaction of the corresponding aromatic aldehyde of the Formula ##STR4## with hydantoin of the Formula I to yield the corresponding 5-arylidene hydantoin of the Formula ##STR5## As the condensing agent in acetic acid sodium acetate may be used or in pyridine as solvent, secondary amines (e.g. diethyl amine, piperidine) can be used [E. Ware: Chem. Rev. 46, 403 (1950); G. Billek: Monatsch. 92, 352 (1961)].
The condensation reaction can also be carried out in aqueous medium in the presence of ethanol amine (cholamine)--see U.S. Pat. No. 2,861,079.
In the next step of the synthesis the 5-arylidene-hydantoin of the Formula III is reduced into the corresponding 5-aryl-methyl-hydantoin of the Formula ##STR6##
The reduction can be carried out with hydrogen iodide/red phosphorous, or hydrogen iodide in glacial acetic acid or by catalytic hydrogenation [E. Ware: Chem.Rev. 46, 403 (1950)]. As the catalyst palladium/charcoal or platinum oxide in alcoholic medium (methanol or ethanol) can be used [M. L. Sethi et al.: J.Pharm.Sci. 62, 1802 (1973)] or Raney-nickel can be applied in methanolic solution under a pressure of 720 atm. at 85.degree. C. [U.S. Pat. No. 2,479,065] or in aqueous medium [H. P. Ward: J.Am.Chem.Soc. 74, 4212 (1952)].
The 5-aryl-methyl-hydantoin of the Formula IV can be converted by hydrolysis into the corresponding DL-.beta.-aryl amino acid of the Formula V. The hydantoin ring can be hydrolysed in acidic medium, e.g. by means of 60% sulfuric acid [L. H. Goodson et al.: J.Org.Chem. 25, 1920 (1960)] or with the aid of 57% hydrogen iodide/red phosphorous [H. L. Wheelerm, C. Hoffman: Am.Chem.J.: 45, 568 (1911); C.A. 5, 2072].
Alkaline hydrolysis is however generally much favorable. For this purpose barium hydroxide can be used [H. L. Wheeler, C. Hoffman: Am.Chem.J. 45 568 (1911); CA 5 2072; R. Gaudri: Can.J.Research 26B 773 (1948); H. Finkbeiner: J.Org.Chem. 30 3414 (1965)], or sodium hydroxide can be applied [E. Pierson et al: J.Am.Chem.So. 70 1450 (1948); M. Matsui, M. Nishio: Agr.Biol.Chem. (Tokyo) 28 710 (1964); K. Okubo, Y. Izumi: Bull.Chem.Soc.Jap. 43 1541 (1970); M. L. Sethi et al.: J.Pharm.Sci. 62 1802 (1973)] in concentrated aqueous solution. Several 5-substituted hydantoin derivatives can be hydrolyzed in an autoclave at (180.degree. C. for 90 minutes) to yield the corresponding amino acid in a solution of Na.sub.2 MoO.sub.4.2H.sub.2 O (KOKAI No. 74-116,008).
L-amino acids can be directly formed by enzymatic hydrolysis of the corresponding racemic 5-substituted hydantoins [U.S. Pat. No. 4,016,037; KOKAI Nos. 77-18,837 and 78-34,990; G. Marcel et al: Bull.Soc.Chim.Fr. 1-2 Pt.2 91(1980)].
The reaction of glycine and urea seems to be the most preferred industrial scale synthesis of hydantoin. The reaction carried out in the melt is unsuitable for industrial scale production because of the low yields and technical problems. It is preferred to carry out the reaction in aqueous medium. When preparing arylidene hydantoines, it is highly preferred to work in an aqueous medium in the presence of ethanol amine. A comparison with the glacial acetic acid/sodium acetate method shows that the yield is higher and the costs are lower.
The saturation of 5-arylidene hydantoins can be carried out most advantageously in the presence of a Raney-nickel because this catalyst is the cheapest and the yields are also higher.
Hydrogenation can be carried out preferably in a diluted sodium hydroxide solution since in this system the solubility conditions are better than in alcohols.
The barium hydroxide hydrolysis method suggested as preferable for the splitting of the hydantion ring has several drawbacks:
a. a part of the starting material remains unreacted and unchanged;
b. on removing the barium ions the solution is acidified with sulfuric acid and a finely distributed barium sulfate precipitate formed causes significant losses-due to adsorption.
Hydrolysis carried out with sodium hydroxide results in certain cases only the corresponding hydantoin acid. Acidic hydrolysis is unsuitable because of the low yields.